Asthma is a pulmonary condition characterized by airway inflammation, airway hyperresponsiveness, and reversible airway obstruction. During asthmatic episodes, afflicted individuals often experience labored breathing, wheezing, and coughing. Of the estimated 20 million asthma patients in the United States, there are about six million children under 18 years of age and over one million children under five years of age with asthma (National Health Interview Survey, 2004). Asthma in children has increased dramatically in both numbers and severity over the last 15 years.
Nearly all pediatric asthma patients require nebulizers for administration of steroid therapy. This is due to either a lack of the breath coordination needed for pressurized metered-dose inhalers (pMDIs) or a lack of the lung capacity needed to use dry powder inhalers (DPIs). Formulations that undergo nebulization are dispersed in air to form an aerosol of very fine liquid droplets suitable for inhalation into the lung. Nebulizers typically use compressed air, piezoelectric or servomechanically generated ultrasonic waves, or a vibrating mesh to create the mist of the droplets, and may also have a baffle to remove larger droplets from the mist by impaction. A variety of nebulizers are available for this purpose, such as soft mist nebulizers, vibrating mesh nebulizers, ultrasonic nebulizers, jet nebulizers, and breath-actuated nebulizers. Examples of commercially available nebulizers include the AERONEB™ and AERONEB GO™ nebulizers (Aerogen, San Francisco, Calif.); PARI nebulizers, including the PARI LC PLUS™, PARI BOY™ N, PARI eflow, PARI LC SINUS, PARI SINUSTAR™, PARI SINUNEB, and PARI DURANEB™ nebulizers (PARI Respiratory Equipment, Inc., Monterey, Calif.); MICROAIR™ nebulizer (Omron Healthcare, Inc, Vernon Hills, Ill.); HALOLITE™ nebulizer (Profile Therapeutics Inc., Boston, Mass.); RESPIMAT™ nebulizer (Boehringer Ingelheim Ingelheim, Germany); ERODOSE™ nebulizer (Aerogen, Inc., Mountain View, Calif.); OMRON ELITE™ (Omron Healthcare, Inc., Vernon Hills, Ill.); OMRON MICROAIR™ (Omron Healthcare, Inc, Vernon Hills, Ill.); MABISMIST™ II nebulizer (Mabis Healthcare, Inc, Lake Forest, Ill.); LUMISCOPE™ 6610 nebulizer; (The Lumiscope Company, Inc., East Brunswick, N.J.); AIRSEP MYSTIQUE™ nebulizer, (AirSep Corporation, Buffalo, N.Y.); ACORN-1 and ACORN-11 (Vital Signs, Inc, Totowa, N.J.); AQUATOWER™ nebulizer (Medical Industries America, Adel, IA); AVA-NEB (Hudson Respiratory Care Incorporated, Temecula, Calif.); AEROCURRENT™ nebulizer utilizing the AEROCELL™ disposable cartridge (AerovectRx Corporation, Atlanta, Ga.); CIRRUS (Intersurgical Incorporated, Liverpool, N.Y.); DART (Professional Medical Products, Greenwood, S.C.); DEVILBISS™ PULMO AIDE (DeVilbiss Corp; Somerset, Pa.); DOWNDRAFT™ (Marquest, Englewood, Colo.); FAN JET (Marquest, Englewood, Colo.); MB-5 (Mefar, Bovezzo, Italy); MISTY NEB™ (Baxter, Valencia, Calif.); SALTER 8900 (Salter Labs, Arvin, Calif.); SIDESTREAM™ (Medic-Aid, Sussex, UK); UPDRAFT-II™ (Hudson Respiratory Care; Temecula, Calif.); WHISPER JET™ (Marquest Medical Products, Englewood, Colo.); AIOLOS™ (Aiolos Medicnnsk Teknik, Karlstad, Sweden); INSPIRON™ (Intertech Resources, Inc., Bannockburn, Ill.); OPTIMIST™ (Unomedical Inc., McAllen, Tex.); PRODOMO™ and SPIRA™ (Respiratory Care Center, Hameenlinna, Finland); AERx™, Essence™, and Ultra™ nebulizers (Aradigm Corporation, Hayward, Calif.); SONIK™ LDI Nebulizer (Evit Labs, Sacramento, Calif.); and SWIRLER® Radioaerosol System (AMICI, Inc., Spring City, Pa.). Exemplary vibrating membrane, mesh or plate nebulizers are described by R. Dhand (Respiratory Care, (December 2002), 47(12), p. 1406-1418). In use, the nebulized formulation is administered to the individual via a mouthpiece or mask. Presently, Pulmicort Respules® ampules (Astrazeneca, Wilmington, Del.) are the only FDA approved nebulized steroid product on the market for the treatment of pediatric asthma.
Low patient compliance is a generally known problem with nebulized drugs. This is primarily due to the amount of time required for nebulizing the drug, which can last up to 30 minutes or longer, depending on such factors as the volume of liquid formulation to be nebulized, the particular active agent being nebulized, the concentration and surface tension of the active agent in the formulation, and the resulting viscosity of the formulation. Other factors include the condition or symptom being treated, and whether the active agent is present as a solution or suspension. Active agent formulations are generally supplied as nominal 2.0 ml volumes with solution or suspension viscosities ranging from that of water, to 100 times the viscosity of water. These typically require about four to about 30 minutes to nebulize, with the nebulization time increasing as the viscosity increases from that of water. If the formulation is a suspension, an additional 15% to 30% longer time is required to nebulize than solution formulations with comparable viscosities due to the added energy required to from droplets containing suspended particulates. Children and adults who become impatient because of lengthy nebulization times often stop treatment prematurely. This can lead to further non-compliance since the inadequate dose will likely fail to provide adequate therapy, and thus discourage further use of the nebulizer treatment regimen.
Another issue with currently available nebulizer ampules relates to settling of the drug during their extended storage. Thus, prior to use, the ampules are shaken to re-disperse the drug within the formulation. In addition to most ampules lacking sufficient headspace to easily facilitate re-dispersion upon shaking, shaking can lead to unwanted drug adherence to the interior surface of the ampules.
Consequently, new containers, kits, and methods for delivering one or more unit doses of an active agent via nebulization for treating asthma and other pulmonary conditions, as well as allergic and inflammatory conditions would be useful. Specifically, containers capable of improving formulation stability would be desirable. Containers that provide more efficient delivery of formulations would also be desirable.